Stäubert Claudia, Tarnow Patrick, Brumm Harald, Pitra Christian, Gudermann Thomas, Grüters Annette, Schöneberg Torsten, Biebermann Heike, Römpler Holger
Institute of Biochemistry, Molecular Biochemistry, Medical Faculty, University of Leipzig, Johannisallee 30, 04103 Leipzig, Germany.
Endocrinology. 2007 Oct;148(10):4642-8. doi: 10.1210/en.2007-0138. Epub 2007 Jul 12.
More than 70 missense mutations have been identified in the human melanocortin 4 receptor (MC4R), and many of them have been associated with obesity. In a number of cases, the causal link between mutations in MC4R and obesity is controversially discussed. Here, we mined evolution as an additional source of structural information that may help to evaluate the functional relevance of naturally occurring variations in MC4R. The sequence information of more than 60 MC4R orthologs enabled us to identify residues that are important for maintaining receptor function. More than 90% of all inactivating mutations found in obese patients were located at amino acid positions that are highly conserved during 450 million years of MC4R evolution in vertebrates. However, for a reasonable number of MC4R variants, we found no correlation between structural conservation of the mutated position and the reported functional consequence. By re-evaluating selected mutations in the MC4R, we demonstrate the usefulness of combining functional and evolutionary approaches.
在人类黑皮质素4受体（MC4R）中已鉴定出70多种错义突变，其中许多与肥胖有关。在许多情况下，MC4R突变与肥胖之间的因果关系存在争议。在此，我们挖掘进化作为结构信息的额外来源，这可能有助于评估MC4R中自然发生变异的功能相关性。60多个MC4R直系同源物的序列信息使我们能够鉴定出对维持受体功能很重要的残基。在肥胖患者中发现的所有失活突变中，超过90%位于在脊椎动物4.5亿年的MC4R进化过程中高度保守的氨基酸位置。然而，对于相当数量的MC4R变体，我们发现突变位置的结构保守性与报道的功能后果之间没有相关性。通过重新评估MC4R中的选定突变，我们证明了结合功能和进化方法的有用性。
